AUTHOR=Shah Idrees A. , Prasad Hari , Banerjee Sanghita , Kurien Reuben Thomas , Chowdhury Sudipta Dhar , Visweswariah Sandhya S. 

TITLE=A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.1058057

DOI=10.3389/fgene.2022.1058057

ISSN=1664-8021

ABSTRACT=<p><bold>Introduction:</bold> Hereditary pancreatitis (HP) is a rare debilitating disease with incompletely understood etio-pathophysiology. The reduced penetrance of genes such as PRSS1 associated with hereditary pancreatitis indicates a role for novel inherited factors.</p><p><bold>Methods:</bold> We performed whole-exome sequencing of three affected members of an Indian family (Father, Son, and Daughter) with chronic pancreatitis and compared variants with those seen in the unaffected mother.</p><p><bold>Results:</bold> We identified a novel frameshift mutation in exon 11 of <italic>TRPV6</italic> (c.1474_1475delGT; p.V492Tfs*136), a calcium channel, in the patients. Functional characterization of this mutant <italic>TRPV6</italic> following heterologous expression revealed that it was defective in calcium uptake. Induction of pancreatitis in mice induced <italic>Trpv6</italic> expression, indicating that higher expression levels of the mutant protein and consequent dysregulation of calcium levels in patients with chronic pancreatitis could aggravate the disease.</p><p><bold>Discussion:</bold> We report a novel frameshift mutation in TRPV6 in an Indian family with HP that renders the mutant protein inactive. Our results emphasize the need to expand the list of genes used currently for evaluating patients with hereditary pancreatitis.</p>